Polybrominated Diphenyl Ethers (PBDEs) flame retardants are considered a source of emerging environmental contaminants. These chemicals leach into the atmosphere and dust from the household products in which they were used. PBDEs are lipid soluble and as such, accumulate within fatty tissues within the human body. These compounds are endocrine disrupting chemicals with a structure very similar to thyroid hormones, although the molecular mechanism(s) by which PBDE modifies thyroid hormone function is (are) not clear. Disruptions in thyroid hormone function are associated with pathological conditions of bone development and remodeling including osteoporosis and it is possible that chronic PBDE exposure may be detrimental to bone health. We have observed that PBDE decreases bone cell-specific gene expression and may also have an impact on bone mineralization and cortical thickness in young rats exposed to relatively low doses during their first seven weeks of postnatal development. We hypothesize that PBDEs interfere with normal bone growth and remodeling due to their activity as thyroid hormone receptor 11 (TR11) antagonists in immature and mature bone forming cells (osteoblasts). The first aim to test this hypothesis is to determine if PBDE impairs osteogenesis and/or osteoblast function by antagonizing thyroid hormone receptor-mediated gene expression. We will use cell culture-based assays that measure gene expression, enzyme activity and calcium deposition in cultured bone cell lines exposed to the penta class of PBDE (penta-BDE) congeners. We will also determine the binding affinities of penta-BDE affinity for thyroid hormone receptors and use transactivation assays and ChIP to measure the ability of penta-BDE to modify thyroid hormone receptor- mediated transcription. In addition, we will test the ability of thyroxine and genetic constructs expressing constitutively active thyroid hormone receptors to "rescue" PBDE-mediated aberrations in cellular processes. The second Aim of this proposal is to characterize the effects that PBDE exposure has on bone growth and remodeling during the life stages of mice. The objective of this aim will be met through the implementation of a toxicological study that will measure bone growth and remodeling as a function of PBDE dose in mice exposed to three different sub-lethal doses of penta-BDE from postnatal day one (PN-1) through early adulthood (PN-60). Bone health will be examined using ex vivo imaging of bone densities, histological examination and analysis of bone marrow populations. Together, these studies are expected to provide novel information regarding the mechanisms underlying the continued risk that exposure to these prevalent environmental contaminants has on bone growth and maintenance in children and adult populations. PUBLIC HEALTH RELEVANCE: The studies described within this application will provide novel insight into the thyroid-disrupting effects of PBDE flame retardants on bone health. With the incidence of bone disease such as osteoporosis as high as 50% in postmenopausal woman, it is important to gain a scientific understanding of the toxic effects of PBDE exposure to aid in the development of governmental regulatory and remediation policies that will limit contamination in the environment and population.